Are You Confident of the Diagnosis?

Pellagra is classically described as the 4 D's in order of symptoms starting: diarrhea (watery, but may contain pus or blood), dermatitis, dementia, death. Three 3 P's also apply: photosensitive, painful, pruritic.

Pellagra is the clinical manifestation of Vitamin B3 (niacin) deficiency. Early cutaneous findings, like many skin diseases, early cutaneous findings, and especially nutritional deficiencies, progressively evolve and change to disease.

Characteristic findings on physical examination

Acute pellagra resembles a symmetrical sunburn in that the skin is red with some blisters that may develop and/or coalesce; subsequently, these often exfoliate, leaving large areas of denuded epithelium. An important feature differentiating pellagra from a true burn is that exacerbation occurs after re-exposure to sunlight. The dorsa of the hands and other areas of photo distribution and friction are more frequently involved and may symptomatically have edema, pruritus and burning resembling a sunburn. However, these symptoms are more than one would expect at a given amount of sun exposure.

This eruption, especially if recurrent, can evolve into red, followed by brown, then black hemorrhage that becomes hard, fissured and easily removed. Especially in cases with more exacerbations and chronicity, the area becomes hyperkeratotic with a darkly pigmented skin appearance.

Locations of involvement include dorsal hands especially, as well as other photodistributed areas; frictional areas like perineum and inframammary folds; oral/ gastrointestinal with sore mouth, red tongue, flat papillae on tongue and gastrointestinal (GI) ulcers with endoscopy.

Expected results of diagnostic studies

Lab tests are important because pellagra often co-exists with other nutritional deficiencies involving vitamins and minerals. Important tests include complete blood count (CBC), low protein, and low urinary N-methylnicotinamide levels; other labs to consider for differential diagnosis include antinuclear antibodies (ANA), zinc, complete metabolic panel (especially glucose) and glucagon in particular.

Atopic dermatitis (AD) presents more diffusely and is located typically more proximally in addition to the dorsal hands. The systemic symptoms of pellagra would be more prevalent and have more oral enanthems than AD. However, some patients restrict diets in AD and there may be some overlap, especially considering that niacin is involved in the biosynthesis of lipids (ceramides) that are vital to barrier function.

Drug eruptions may appear identical to acute pellagra as mentioned, especially photosensitizing medications. The history should help elucidate which would be more likely. Hartnup disease is a genetic condition in which amino acids, tryptophan in particular, are not absorbed effectively and thus cannot be used, thereby manifesting with a "pellagra-like" condition. This presents much earlier in life.

Polymorphous light eruption (PMLE) and systemic lupus erythematosus (SLE) flares characteristically affect the malar region, where a subacute lupus erythematosus flare tends to look like acute pellagra. SLE could also have oral, psychomotor, and systemic symptoms. A thorough history and physical with some laboratory evaluation (CBC, ANA) could be considered if there seemed to be more of an overlap. However, the combination of symptoms of oral, diffuse cutaneous involvement, especially on the wrist and feet, would lead one towards diagnosis of pellagra versus that of SLE or PMLE. Additionally, a facial flare of pellagra almost always coincides with exanthems elsewhere.

PCT presents with as blisters erythema particularly on the wrist of a photodistributed area and may have recurrent flares. However, these flares do not typically exhibit the amount of dyschromia and hyperkeratosis seen with pellagra. A biopsy with or without immunofluorescence should help differentiate these two entities.

Though not mentioned in most textbooks, in the author's opinion NME/AE resembles pellagra. NME and AE have the same distribution and look identical pathologically. NME is typically caused by glucagonomas and AE is typically caused by zinc deficiency. It is important to note that many nutritionally deficient patients do not have a deficiency in just one vitamin or mineral and many overlapping scenarios exist. Thus these entities should be considered together and replacement therapy should be administered simultaneously. Pellagra, compared to AE, involves the neck (Casal necklace) and has more proximal hand involvement than AE, whereas AE may involve the perineum more commonly than pellagra. As mentioned, overlap does exist and should be considered together especially in alcoholic or anorexia patients.

Who is at Risk for Developing this Disease?

Pellagra is the clinical manifestation of vitamin B3 deficiency. This is uncommon in the developed world but involves the deficient intake, absorption, or use of niacin or tryptophan. Common scenarios include alcoholism, chronic gastrointestinal diseases, cirrhosis, fad or restrictive (atopic dermatitis) diets, and psychiatric conditions that preclude a normal, effective diet (anorexia or bulimia).

What is the Cause of the Disease?

Etiology

Many different scenarios exist for the development of pellagra but they all stem from a deficiency in niacin or vitamin B3. Primary pellagra is caused by lack of dietary intake; historically in poverty-stricken areas where only maize (corn) was consumed. It may also be due to a deficiency in tryptophan, which is found in soybeans, meat, poultry, fish and eggs. Secondary causes are from inadequate and/or decreased absorption or effective processing of the vitamin.

Pathophysiology

Tryptophan is converted to niacin within the body using vitamin B6. Thus drugs that deplete vitamin B6 would inhibit that conversion. Isoniazid competes with niacin and thus can induce a pellagra-like condition as well. Increased tryptophan metabolism can cause pellagra or a pellagra-like condition. For example, HIV can stimulate a pellagra-like condition in which tryptophan levels decreased. Carcinoid syndrome increases conversion of tryptophan to serotonin and diverts tryptophan from converting to niacin, thereby causing a pellagra-like disorder.

Systemic Implications and Complications

Untreated pellagra can result in death from multiorgan failure. As mentioned, neuropsychiatric effects can be seen, such as anger, apathy, weakness, anxiety, depression, delusions, and stupor. As an example, hyperactive tendon reflexes can occur secondary to pyramidal tract involvement.

Treatment Options

Oral nicotinic acid in doses of 50mg by mouth three times a day has been noted to improve symptoms in 2-3 days. Even in the 1940s, practitioners noted improvement of the GI, neurologic and oral symptoms within 24 hours of administration of the vitamin. This should be continued for 2-3 weeks, along with appropriate nutritional counseling for future prevention. If oral intake is not possible, then nicotinamide intramuscularly can be given three times a day at 50-100mg for 3-4 days, at which time oral administration of the vitamin can be considered.

Optimal Therapeutic Approach for this Disease

Functional niacin is the only way to improve the condition as described in the treatment options section (2-3 weeks of nicotinic acid 50mg three times a day). If the lack of tryptophan conversion to niacin is the cause, and it is a reversible process, this should be corrected (ie, stop the isoniazid (INH) therapy as soon as indicated, remove the carcinoid tumor).

Referral to appropriate caregivers for stopping the vicious circle of alcoholism or anorexia would be vital to long-term improvement. As mentioned, nutritional deficiencies normally involve more than one vitamin or mineral deficiency, so a high-protein diet and complex B vitamin along with a multivitamin supplement should be considered.

Patient Management

Replacement of functional niacin is the only way to improve the condition in the long term. Short-term therapy of moderate topical steroids (triamcinolone 0.1% ointment) to decrease the inflammation that exist might be helpful, but simple lubrication with any lubricant (CeraVe, Aquaphor, Vaseline, or even Crisco if money is tight) should be considered.

Unusual Clinical Scenarios to Consider in Patient Management

The increasing number of weight loss surgeries being performed in the developed countries is leading to a rise in nutritional deficiencies. Thus, a history of these procedures should encourage the performance of a thorough history and physical exam looking for findings of pellagra or other nutritional deficiencies, especially in patients with a history of chronic dermatitis.

(Article looking at all nutrients in patients with Crohn's. They found 77% had low niacin levels. This demonstrates chronic GI inflammation/ irritation can lead to nutritional deficiencies in general.)